Summary: Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis, decompensated liver disease and hepatocellular carcinoma (HCC) worldwide. Globally there are an estimated 170 million persons with HCV. In the United States (U.S.), there are 4.1 million persons who are anti-HCV positive, 3.2 million of whom have chronic infection based on the detection of HCV RNA in serum. In 2001, chronic liver disease was the 12th leading cause of death in the U.S. These figures underscore the magnitude and impact that chronic HCV infection has on global and US public health. The natural history of chronic HCV infection has been difficult to study. The protracted and silent course of infection, the absence of large cohorts of persons known to be infected, and the wide variability in outcome are major obstacles to natural history studies. Five to twenty-five percent of HCV-infected persons will develop cirrhosis over a 25-30 year period but some patients remain asymptomatic, without significant liver disease for many decades if not for life. Knowledge of the rate of progression among individuals who have not developed cirrhosis is unknown. An equally important and related issue is the clinical assessment of disease severity. Unfortunately, there are no good laboratory markers of disease severity and liver biopsy, the accepted gold standard for assessing disease severity is imperfect. Non-invasive methods to assess disease severity are highly desirable for the clinicians diagnostic toolbox. The optimal treatment for chronic HCV infections results in sustained eradication of the virus in 54% to 56% of persons. It is evident that a large number of persons do not respond to therapy. The current state of therapy is inadequate, expensive, and cannot be applied to a substantial proportion of affected individuals due to problematic side effects. Therapeutic options for non-responder patients and persons who do not qualify for interferon-based regimens are limited. Thus newer, safer and more effective therapies are urgently needed for chronic HCV infection. Hypotheses/problems addressed: 1) Define the host, viral and environmental factors that determine the natural history and outcome of HCV infection. To address this problem, we have created a large database of untreated patients with chronic HCV (n700) and have analyzed this database to identify factors that affect the natural history of chronic HCV infection. We have published 3 studies on this cohort, identifying clinical factors and candidate genes associated with fibrosis progression. To further define factors associated with fibrosis progression and clinical outcome of chronic hepatitis C, we prospectively monitored a large, well characterized cohort of over 1000 patients who participated in a randomized, controlled, multi-center trial of long-term peginterferon versus no therapy for patients with advanced HCV infection (HALT-C-see below) for 8 years. Important data describing the natural history of advanced chronic hepatitis C has been derived from this study. This included the observation that 31% of control patients developed a clinical outcome over 4 years. Liver-related death and/or liver transplantation were common outcomes in person who remained viremic. In contrast, patients who clear the virus had a significantly reduced rate of clinical outcomes. More recently, we have developed a prediction model which demonstrates that both the baseline value and the rapidity in change of the value of routine laboratory variables appear to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. Finally, we are validating the usefulness of a new technology, ultrasound elastography (Fibroscan), to non-invasively assess hepatic fibrosis. Results which will be presented at the annual AASLD meeting in November 2011, revealed that the device has a 96% accuracy for prediction of cirrhosis. Studies are ongoing to compare Fibroscan and MRI elastography to liver biopsy, and plasma will be stored for future proteomic analysis. Our goal is to develop a series of blood and imaging test that will obviate the need for liver biopsy in most patients with chronic HCV infection. 2) Develop and evaluate novel, safer and more effective therapies for chronic viral hepatitis. Although therapy of chronic HCV infection has improved over the last decade, it remains sub-optimal. Close to fifty percent of treated patients fail to achieve sustained clearance of HCV. Options for patients who fail therapy are limited. Ribavirin, a guanosine nucleoside analogue is critically important for the success of therapy for CHC. Several post-hoc analyses and one pilot study have suggested that higher doses of ribavirin may be associated with higher rates of viral clearance. Accordingly, we have initiated an open label study to evaluate the safety and efficacy of high dose ribavirin in combination with standard dose peginterferon alfa-2a for non-responder and relapser patients with CHC. Viral kinetics in the high dose cohort will be compared to standard dose ribavirin historical controls treated in other LDB protocols. Twenty patients have been enrolled to date and 14 have completed therapy. 3. Elucidate the viral pathogenesis of chronic HCV infection and mechanisms of action of anti-viral therapy The conduct of clinical trials over the last 30 years has allowed the LDB to acquire invaluable clinical material (patient serum, liver tissue and lymphophocytes) to which state of the art laboratory techniques can be applied to address issues of the pathogenesis of HCV infection and the mechanisms of action of antiviral therapy. The mechanism of action of ribavirin is unknown. Error catastrophe and lethal mutagenesis due to an increase in the viral mutation rate has been shown to be a possible mechanism of ribavirin in poliovirus, bovine diarrhea virus and GBV-B, viruses very similar to HCV. We have previously shown that ribavirin use is associated with an early, transient increase in the mutation rate of HCV but this effect was not observed at later time points. This suggests that lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for chronic HCV infection. Our plan is to extend this investigation, examining the effects of higher doses of ribavirin and the effects of the combination of ribavirin and interferon on viral mutation rate.